Abstract:

Objective    To establish a population pharmacokinetic（PPK）model of levetiracetam in Chinese children with epilepsy.Methods    A total of 250 data from 220 epileptic children were analyzed.Levetiracetam concentrations were determined by the HPLC method.PPK model of levetiracetam was established using NONMEM，a population pharmacokinetic computer program，according to one-compartment model with first-order absorption and elimination.To validate a model，the normalized prediction distribution errors（NPDE） method was used.Results    Regression equation of the base model of levetiracetam was obtained，ie，clearance（CL/F）=1.56×EXP ［ETA（1）］，volume of distribution（V/F）was fixed 20，and Ka = EXP［ETA（3）］，and that of the final model was as follows：CL/F（L/h）=1.35×（WEIGHT/25.26）0.578，V/F（L）=20，KA（/h）=2.11×EXP［ETA（3）］.The final PPK model was demonstrated to be stable and effective in the prediction of serum levetiracetam concentrations by NPDE.Conclusion    A one-compartment mixture model with first-order absorption adequately describes the levetiracetam concentrations.Weight is identified as a significant covariate on levetiracetam clearance in this study.

Key words: levetiracetam, population pharmacokinetics, epilepcy, children

摘要：

目的    建立中国癫痫儿童左乙拉西坦（LEV）群体药代动力学（PPK）模型，指导临床合理用药。方法    分析2009年6月至2010年12月北京大学第一医院小儿神经门诊及病房收集的220例服用LEV癫痫患儿的250个LEV血药浓度数据，使用非线性混合效应模型（NONMEM）软件，按照一室一级吸收和消除模型，建立我国癫痫患儿LEV的PPK模型。使用正态化预测分布误差（NPDE）方法验证模型。结果    LEV PPK基础模型：清除率 （CL/F）＝1.56 × EXP［ETA（1）］ L/h，表观分布容积（V/F）被固定为20 L，吸收速率常数（KA）＝EXP［ETA（3）］ /h；最终模型：CL/F＝［1.35×（体重/25.26）0.578］L/h，V/F＝20 L，KA＝2.11×EXP［ETA（3）］/h；CL/F、V/F和KA群体值分别为1.35 L/h、20 L和2.11/h。经过NPDE方法验证，所建立的最终模型有良好稳定性和预测效能。结论    本文建立了中国癫痫患儿LEV PPK模型，模型通过验证及预测效能，可用于指导临床用药。体重是对清除率影响最明显的协变量。

关键词: 左乙拉西坦, 群体药代动力学, 癫痫, 儿童